The main objective of the proposed research is to validate through experimental studies a new approach to combination chemotherapy--that is, to study the effects of a combination of antitumor agents which are specific inhibitors of the individual components of ribonucleotide reductase. These studies will determine if the combination of specific inhibitors of the individual components of a multi-components of a multi-component enzyme result in inhibition which is additive, synergistic or antagonistic. These studies with the combination of drugs will be carried out using the partially-purified components to reconstitute the ribonucleotide reductase activity, in tumor cells in short-term culture cells growing in culture, and in tumor-bearing mice. The results of these studies will provide experimental data required for the design of protocols of combinations of drugs which are directed at the key metabolic site catalyzed by ribonucleotide reductase.